Diabetes is a disease associated with high levels of sugar in the blood and is classified as Type 1 diabetes in which, the body makes little or no insulin or Type 2 diabetes. Type II diabetes is responsible for most of diabetes cases and is also associated with of high obesity rates. Diabetes affects more than 20 million Americans. Over 40 million Americans have pre-diabetes (early type 2 diabetes). The high blood sugar levels can cause several symptoms, including blurry vision, excess thirst, fatigue etc. A major pathophysiological factor in Type II diabetes is decreased glucose utilization in peripheral tissues, such as skeletal muscles and fat depots. Several clinical observations in diabetic patients suggest that hyperglycemia per se may contribute and even worsen this phenomenon. Current pharmacological treatments of type 2 diabetes include mono- and combination therapies of various oral antidiabetic drugs. In many cases these therapies fail to achieve optimal glycemic control.
Thus, there is a need to develop novel antihyperglycemic drugs, including those that are capable of augmenting the insulin secretory capacity of β-cells and/or increase the rate of glucose uptake in insulin sensitive tissues.
General Description
The present invention provides a compound having the general formula (I):

wherein
X, Y, Z are each independently selected from the group consisting of N, S, O, CH, C—SH, NH, N-linker-R1, C-linker-R1;
W1, W2, W3, W4 are each independently selected from the group consisting of N, CR2;
linker is independently selected from the group consisting of —S—, —S—S—, —S—(CH2)n—, —NH—, —NH—(CH2)n—, —O—, —SO2—, arylene, heteroarylene;
n is 1 to 5;
R1 is selected from the group consisting of straight or branched C4-C20 alkyl, straight or branched C4-C20 alkenyl, straight or branched C4-C20 alkynyl, each optionally interrupted with at least one NH, C5-C7 saturated cycloalkyl or C5-C7 heteroalkyl ring, C5-C12 aromatic or heteroaromatic ring, each optionally substituted with at least one group selected from —COOH, —NH2, C1-C8 alkoxy, C1-C5 amidyle, C1-C5 carboxyl, halogen;
R2 is independently selected from the group consisting of H, OH, SH, NH2, NO2, halogen, CN, C1-C8 alkoxy, C1-C5 carboxylic acid, straight or branched C1-C8 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C12 alkynyl each optionally substituted by at least one substituent selected from the group consisting of C1-C5 alkoxy, C1-C5 carboxylic acid, OH, SH, NH2, halogen;
provided that at least one of X, Y, and Z is selected from N-linker-R1 or C-linker-R1.
In some embodiments, the alkyl, alkenyl and alkynyl may be optionally interrupted with one or more oxygen, sulfur, including S(═O) and S(═O)2 groups, or NH group along the carbon chain, in some further embodiments the alkyl, alkenyl and alkynyl may be optionally interrupted with at least one NH group.
In yet some further embodiments, the alkyl, alkenyl and alkynyl may be optionally substituted by C1-C5 alkoxy, C1-C5 carboxylic acid, OH, SH, NH2, halogen.
In some embodiments, the C5-C7 saturated cycloalkyl or C5-C7 heteroalkyl ring, C5-C12 aromatic or heteroaromatic ring may be substituted with one or more substituents, in certain embodiments one, two, three or four substituents, where the substituents are selected from —COOH, —NH2, C1-C8 alkoxy, C1-C5 amidyle, C1-C5 carboxyl, halogen.
In some embodiments X and Z are each independently N or S. In some further embodiments, Y is N-linker-R1 or C-linker-R1. In some yet further embodiments, Y is C-linker-R1.
In some embodiments, the linker is —S—(CH2)n—, —NH—(CH2)n—. According to these embodiments, the group —(CH2)n— wherein n=1 to 5, may encompasses an alkyl, alkenyl and alkynyl as defined herein having at most five carbon atoms. In yet some further embodiments, the linker is —S—S—, —S—CH2—.
In some embodiments, R1 is straight or branched C4-C20 alkyl, straight or branched C4-C20 alkenyl, straight or branched C4-C20 alkynyl. In some embodiments, R1 is optionally interrupted with at least one heteroatoms selected from O, S, or NH. In some further embodiments, R1 is optionally interrupted with at least NH.
In some other embodiments, R1 is C5-C7 saturated cycloalkyl or C5-C7 heteroalkyl ring, C5-C12 aromatic or heteroaromatic ring. In some embodiments, R1 is benzothiazole. In some other embodiments, R1 is 1,3-dioxane.
In such embodiments, R1 is optionally substituted with at least one group selected from —COOH, —NH2, C1-C8 alkoxy, C1-C5 amidyle, C1-C5 carboxyl, halogen. In some embodiments, the alkoxy group is an ethoxy group.
In some embodiments, W1, W2, W3, W4 are each independently N. In some embodiments, W1, W2, and W3, are N and W4 is CR2, at times W1, W2, and W4, are N and W3 is CR2, at times W1, W3, and W4, are N and W2 is CR2 and at times W2, W3, and W4, are N and W1 is CR2.
In some further embodiments, each of W1, W2, W3 and W4 is independently CR2. In these embodiments, R2 may be H, OH, SH, NH2, NO2, halogen, CN, C1-C8 alkoxy, C1-C5 carboxylic acid. In some other embodiments, R2 may be straight or branched C1-C8 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C12 alkynyl. In these embodiments, R2 may optionally substituted by at least one substituent selected from the group consisting of C1-C5 alkoxy, C1-C5 carboxylic acid, OH, SH, NH2, halogen.
In some embodiments, R2 is a C1-C8 alkoxy, at times an ethoxy group. In some other embodiments, R2 is OH.
In some embodiments a compound of the invention has the general formula (V):

wherein R1, Linker and R2 are as defined hereinabove.
In further embodiments a compound of the invention has the general formula (VI):

wherein R1 and R2 are as defined hereinabove.
In other embodiments a compound of the invention has the general formula (VII):

wherein R1 and R2 are as defined hereinabove.
In accordance with this aspect, the invention also provides a compound selected from the following list:

The present invention provides in accordance with a second aspect a compound having the general formula (II):

wherein
X1, X2, X3 and X4 are each independently selected from the group consisting of S, O, CH2, CHR3, NH, NR3; provided that at least one of X1 to X4 is O or S;
V1, V2, V3 and V4 are each independently selected from N, C, CH and CR4;
Y and Z are each independently S or O;
R1 and R2 are each independently selected from straight or branched C1-C20 alkyl, straight or branched C2-C20 alkenyl, straight or branched C2-C20 alkynyl, each optionally interrupted with at least one NH; or wherein R1 and R2 together with Y, Z and the carbon atom connecting them a 5 to 10 membered ring; optionally substituted by at least one group selected from straight or branched C1-C10, alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl;
R4 is selected from the group consisting of halogen, straight or branched C1-C20 alkyl, straight or branched C2-C20 alkenyl, straight or branched C2-C20 alkynyl;
R3 is selected from the group consisting of straight or branched C1-C12 alkyl, straight or branched C2-C5 alkenyl, straight or branched C2-C5 alkynyl, —COOH, —NH2, C1-C8 alkoxy, C1-C5 amidyle, C1-C5 carboxyl, C6-C12 aryl, C4-C12 heretroaryl and heterocyclyl, wherein each of aryl, heretroaryl and heterocyclyl is optionally substituted by at least one of alkoxy, alkyl, alkenyl, alkynyl, amino, cyano, halogen, and 1,3-dithian-benzyl.
In some embodiments, at least one of X1 to X4 is O or S, at some further embodiments at least two of X1 to X4 are O or S. In some other embodiments, at least one of X1 to X4 is O or CHR3.
In some embodiments, R3 may be straight or branched C1-C12 alkyl, straight or branched C2-C5 alkenyl, straight or branched C2-C5 alkynyl, —COOH, —NH2, C1-C8 alkoxy, C1-C5 amidyle, C1-C5 carboxyl.
In some further embodiments, R3 may be C6-C12 aryl, C4-C12 heretroaryl and heterocyclyl, wherein each of aryl, heretroaryl and heterocyclyl. In such embodiments, R3 is optionally substituted by at least one of alkoxy, alkyl, alkenyl, alkynyl, amino, cyano, halogen, and 1,3-dithian-benzyl.
As used herein the term “C1-C20 alkyl” is meant to encompass straight or branched alkyl having 1 to 20 carbons, in some embodiments, contain from 4 to 20 carbons, in yet some embodiments from 1 to 8 carbons. As used herein the term “C2-C20 alkenyl” is meant to encompass a straight or branched alkenyl chain having between 2 to 20 carbon atoms, in some embodiments from 4 to 20 carbons, at some further embodiments from 2 to 10 carbons, and at least one double bond. As used herein the term “C2-C20 alkynyl” is meant to encompass a straight or branched alkynyl chain having between 2 to 20 carbon atoms, in certain embodiments, from 4 to 20 carbons, at some further embodiments, from 2 to 12 carbons, and at least one triple bond.
As used herein “alkoxy” refers to an alkyl group bonded to an oxygen atom. At times, the alkyl group may include one to eight carbon atoms, at times between one to five carbon atoms. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like. In certain embodiments, the alkoxy is ethoxy.
The term “halogen” (halo or halide) refers to F, Cl, Br or I.
As used herein, “C5-C7 saturated cycloalkyl” refers to a saturated mono- or multi-cyclic ring system having 5 to 7 carbon atoms. Example of “C5-C7 cycloalkyl” groups include, but are not limited to cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, “heterocycloalkyl” refers to a monocyclic or multi-cyclic non-aromatic ring system having 5 to 7 members, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur. Examples of “heteroalkyl” include, but are not limited to, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
As used herein, “C5-C12 aromatic” refers to aromatic ring systems having 5 to 12 carbon atoms, such as phenyl, naphthalene and the like.
As used herein, “C5-C12 heteroaromatic” refers to heteroaromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furan, thipohene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, thiazolem benzofurna, indole, benzothiophene, benzoimidazole, indazole, benzoxazole, benzoisoxazole, benzothiazole, isobenzfuran, isoidole, purine, pyridine, pyrazine, pyrimidine, pyrisazine, quinoline, quinozaline, quinazoline, isoquinoline.
As used herein, “arylene” refers to a monocyclic or polycyclic, in some embodiments monocyclic, divalent aromatic group, in one embodiment having from 5 to about 20 carbon atoms and at least one aromatic ring, in another embodiment 5 to 12 carbons. Arylene groups include, but are not limited to, 1,2-, 1,3- and 1,4-phenylene. In some embodiments, the arylene group is phenylene, in some further embodiments, the arylene is 1,4-phenylene.
As used herein, “heteroarylene” refers to a monocyclic refers to a divalent monocyclic or multicyclic aromatic ring system, in one embodiment of about 5 to about 15 atoms in the ring(s), where one or more, in certain embodiments 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
The term “C5-C12 aromatic ring” used interchangeably with the term “aryl” as used herein is intended to include carbocyclic aromatic ring systems having between 5 to 12 carbon atoms, such as for example phenyl, naphthyl.
The term “C4-C12 heteroaromatic” used interchangeably with the term “heteroaryl” as used herein is intended to include heterocyclic aromatic ring systems containing 4 to 12 carbon atoms and one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like.
As used herein, the term “heterocycloalkyl” or “heterocyclyl” or the term “heterocyclic” refers to a three to twelve-membered non-aromatic ring being unsaturated or having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO2, O, or N. “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
The compounds of the present invention, as defined above, may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of formulae (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers or as two or more diastereomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Furthermore, the compounds of this invention include mixtures of diastereomers, as well as purified stereoisomers or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the invention, as defined above, as well as any wholly or partially mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
It is also noted that the compounds of the present invention may form tautomers. It is understood that all tautomers and mixtures of tautomers of the compounds of the present invention, are included within the scope of the compounds of the present invention.
In a further aspect, the invention provides a composition comprising a compound of general Formula (I), (II) (III), (IV), (V), (VI) or (VII) as defined herein above, or any salt thereof.
In some embodiments, said composition is a pharmaceutical composition, wherein said salt is a pharmaceutically acceptable salt.
Pharmaceutical compositions of the invention may additionally comprise any other suitable substances such as other therapeutically useful substances, diagnostically useful substances, pharmaceutically acceptable carriers or the like.
In some embodiments a compound or composition of the invention is administered (suitable to be administered) to an adipose tissue of a subject. In some embodiments said compound or composition of the invention is administered directly to an adipose tissue of a subject. In other embodiments said administration is via injection. In other embodiments, said administration is via a transdermal delivery device (for example a patch containing a compound or composition of the invention) at a close proximity to the adipose tissue location of said subject (for example the direct skin or mucosal tissue in contact with said adipose tissue).
Pharmaceutical compositions of the invention comprise a compound of the subject invention in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The auxiliaries must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intra-adipose tissue and intradermal) administration or administration via an implant. The compositions may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing in association compounds used in the invention or combinations thereof with any auxiliary agent. The auxiliary agent(s), also named accessory ingredient(s), include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents, anti-oxidants, and wetting agents.
Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragées or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus or paste. The compositions can further be processed into a suppository or enema for rectal administration.
The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described.
For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use. For transdermal administration, e.g. gels, patches or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration e.g. by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators.
In some embodiments, compositions of the invention include also compositions where the compound of the invention is formulated in a fat emulsion formulation (i.e. formulated in conventional formulation processes to produce an emulation comprising at least one fat component, either from a natural or synthetic source), such as for example Intralipid formulation (in any concentration).
The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.
The invention also includes any salt of a compound of the invention, including any pharmaceutically acceptable salt, wherein a compound of the invention has a net charge (either positive or negative) and at least one counter ion (having a counter negative or positive charge) is added thereto to form said salt. The phrase “pharmaceutically acceptable salt(s)”, as used herein, means those salts of compounds of the invention that are safe and effective for pharmaceutical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, iso nicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
In another aspect there is provided a compound of the invention, as defined herein above, for use as a medicament.
In a further aspect the invention provides a use of a compound of the invention as defined herein above, for the preparation of a medicament.
In some embodiments, said medicament is for the treatment or prevention of a condition, symptom or disease associate with elevated blood glucose levels.
In a further aspect the invention provides a compound of the invention, for use in at least one of increasing the rate of glucose uptake and augment glucose-stimulated insulin secretion. In some embodiments, a compound of the invention is capable of increasing the rate of glucose uptake and augment glucose-stimulated insulin secretion.
In some embodiments, said medicament is for treating or preventing at least one condition selected from hyperglycemia, diabetes, altered insulin secretion, insulin resistance, cardiovascular disorders, obesity and the metabolic syndrome.
In certain embodiments, the condition is associated with hyperglycemia. In some embodiments, the condition is metabolic syndrome. Medical syndrome is a combination of medical disorders that increase the risk to develop cardiovascular disease and diabetes. Metabolic syndrome is also known as metabolic syndrome X, cardiometabolic syndrome, syndrome X and insulin resistance syndrome. In certain embodiments, the condition is associated with cardiovascular disorder.
In some embodiments, the condition is altered insulin secretion. In some other embodiments, the condition is insulin resistance. In some embodiments, the condition is diabetes.
As appreciated, diabetes often referred to as diabetes mellitus (DM) is considered as a group of metabolic diseases associated with high levels of glucose in the blood. At times, the high blood glucose is either due to the fact that the body does not produce enough insulin, or because cells do not respond to the insulin that is produced and secreted.
Type I diabetes mellitus (DM) (previously referred to as “insulin-dependent diabetes mellitus” (IDDM) is a result of the body's failure to produce insulin, and thus often requires the person to inject insulin or wear an insulin pump.
Type II DM (previously referred to as non insulin-dependent diabetes mellitus (NIDDM)) is a result of insulin resistance, in which cells fail to use insulin properly, sometimes combined with partial or an absolute insulin deficiency.
In addition, another type of diabetes is gestational diabetes, occurring in pregnant women without a previous diagnosis of diabetes and develops a high blood glucose level.
According to the present invention, the diabetes is Type I or Type II.
The inventors have found that the compounds developed herein increased the rate of glucose uptake in skeletal muscle cells (L6 myotubes). In addition, the compounds were shown to increase the abundance of glucose transporter-4 (GLUT4) in the plasma membrane of the myotubes. As appreciated, GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle (skeletal and cardiac) that is responsible for insulin-regulated glucose transport into the cell.
Without being bound by theory, the increased translocation of GLUT4 into the plasma membrane may be connected to the increased glucose uptake by the cells.
Thus, in some embodiments, the compounds described herein increase glucose uptake into the cells. In some other embodiments, the compounds described herein increase translocation of GLUT into the plasma membrane.
In was also found by the inventors that the increased rate of glucose uptake in some of the compounds was in an insulin-independent manner. Specifically, the inventors have shown that the novel compounds did not activate AKT/PKB, a key regulator on the insulin transduction pathway.
In skeletal muscles, activated Adenosine monophosphate-Activated Protein Kinase (AMPK) increases the rate of glucose transport and fatty acid oxidation, while in the liver it predominantly increases glucose uptake. These effects lead to increased peripheral glucose disposal and reduced blood glucose levels in hyperglycemic individuals. The enzyme AMPK, which acts as a sensor of cellular energy status, plays a central role in the regulation of glucose transport in skeletal muscles. Several AMPK isoenzymes have been identified, of which AMPKα2 is the abundant one in skeletal muscles. This enzyme is physiologically activated when the AMP:ATP ratio is increased in cells. Activated AMPK promotes the translocation of GLUT-4-containing vesicles to the plasma membrane in a non-insulin-dependent manner. Without wishing to be bound by theory, the compounds described herein were found to induce AMPK activation by inducing Thr172 phosphorylation in AMPK. In some embodiments, the compounds described herein activate AMPK. Thus, these compounds were able to increase the rate of glucose entry to skeletal muscles, even under hyperglycemia conditions. Previously, two large groups of antidiabetic drugs (biguanides and thiazolidinediones) were found to be activators of AMPK. However, side effects, such as lactic acidosis, fluid retention, weight gain and development of tolerance to long-term use, emphasize the need for better tissue- and isoform specific AMPK activators. The compounds defined herein may improve the uptake of glucose into the cells and thus reduce the level of glucose in the blood.
In addition, the compounds defined herein were found to promote the increase of insulin secretion in β-cell in pancreatic islets of Langerhans. Specifically, the inventors have found that the compounds defined herein augments glucose-stimulated insulin secretion. Without being bound by theory, these compounds can use to increase the rate of glucose uptake in insulin sensitive tissues.
Thus, the compounds defined herein may be used as insulin secretagogues, namely triggering insulin secretion by direct action on the pancreatic β cells.
In addition, the inventors have found that compounds defined herein may possess dual function: on one hand they increase the rate of glucose uptake in skeletal muscle cells, and on the other hand, augment glucose-stimulated insulin secretion from cultured β-cells. Specifically, it was found by the inventors that both bis(6-ethoxybenzo[d]thiazol-2-yl)disulfane and 2-(propylthio)benso[d]thiazol-6-ol) have such dual function.
Without being bound by theory, the combination of increased insulin secretion and augmented glucose uptake in skeletal muscles may synergistically increase peripheral glucose disposal in hyperglycemic individuals. In certain embodiments, the condition is obesity.
The term “obesity” is meant to encompass is a condition in a subject having excess body fat. It is defined by body mass index (BMI) and further evaluated in terms of fat distribution via the waist-hip ratio and total cardiovascular risk factors. Additional parameters measuring extent of obesity are percentage body fat and total body fat. Subjects suffering from obesity have a BMI value of above 25. In some embodiments the term “obesity” includes subjects having BMI values of between about 25.0 to about 29.9 (overweight), in some further embodiments between about 30.0 to about 34.9 (class I obesity), in yet further embodiments between about 35.0 to about 39.9 (class II obesity), in further embodiments above 40.0 (class III obesity), in other embodiments between about 40 to about 49.9 (morbid obesity) and in other embodiments ≧50 (super obesity).
In another one of its aspects the invention provides a method of treatment or prevention of at least one condition selected from hyperglycemia, diabetes, altered insulin secretion, insulin resistance, cardiovascular disorder, obesity and metabolic syndrome X; said method comprising administering to a subject in need thereof an effective amount of a compound of general formula (I), formula (II) or formula (III), as defined herein above.
The term “treatment” as used herein refers to the administering of a therapeutic amount of a compound and/or a composition of the present invention which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease or condition, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease or condition, to delay the onset of said progressive stage, to lessen the severity or cure the disease or condition, to improve survival rate or more rapid recovery, or to prevent the disease or condition form occurring or a combination of two or more of the above.
The “effective amount” for purposes disclosed herein is determined by such considerations as may be known in the art. The amount must be effective to achieve the desired therapeutic effect as described above, depending, inter alia, on the type and severity of the disease to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half life in the body, on undesired side effects, if any, on factors such as age and gender, etc.
According with another aspect, the present invention provides a compound having the general formula (I), for use in treating or preventing at least one condition selected from hyperglycemia, diabetes, altered insulin secretion, insulin resistance, cardiovascular disorder, obesity and metabolic syndrome X:

wherein
X, Y, Z are each independently selected from the group consisting of N, S, O, CH, C—SH, C—NH, —C—OH, —N—SH, NH, N-linker-R1, C-linker-R1;
W1, W2, W3, W4 are each independently selected from the group consisting of N, CR2;
linker is independently selected from the group consisting of —S—, —S—S—, —S—(CH2)n—, —NH—, —NH—(CH2)n—, —O—, —SO2—, arylene, heteroarylene;
n is 1 to 5;
R1 is selected from the group consisting of straight or branched C4-C20 alkyl, straight or branched C4-C20 alkenyl, straight or branched C4-C20 alkynyl, each optionally interrupted with at least one NH, C5-C7 saturated cycloalkyl or heteroalkyl ring, C5-C12 aromatic or heteroaromatic ring, each optionally substituted with at least one group selected from —COOH, —NH2, C1-C8 alkoxy, C1-C5 amidyle, C1-C5 carboxyl, halogen;
R2 is independently selected from the group consisting of H, OH, SH, NH2, NO2, halogen, CN, C1-C8 alkoxy, C1-C5 carboxylic acid, straight or branched C1-C8 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C12 alkynyl each optionally substituted by at least one substituent selected from the group consisting of C1-C5 alkoxy, C1-C5 carboxylic acid, OH, SH, NH2, halogen.
According with another aspect, the present invention provides a compound of general formula (IV), for use in the treatment or prevention of at least one condition selected from hyperglycemia, diabetes, altered insulin secretion, insulin resistance, cardiovascular disorder, obesity and metabolic syndrome X:
wherein
V1, V2, V3, V4, V5 and V6 are each independently selected from N, C, CH and CR3;
Y and Z are each independently S or O;
R1 and R2 are each independently selected from straight or branched C1-C20 alkyl, straight or branched C2-C20 alkenyl, straight or branched C2-C20 alkynyl, each optionally interrupted with at least one NH; or wherein R1 and R2 together with Y, Z and the carbon atom connecting them a 5 to 10 membered ring; optionally substituted by at least one group selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl;
R3 is selected from the group consisting of halogen, straight or branched C1-C20 alkyl, straight or branched C2-C20 alkenyl, straight or branched C2-C20 alkynyl; amidyle carboxy, SO2, cabamate, optionally substituted by 1,3-dithian-benzyl
It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.